As countries across the world continue to face widespread disruption in the face of the COVID-19 pandemic, researchers are racing to identify diagnostics, vaccines and treatments. One of the exciting technologies that researches have turned to in this vital scientific endeavour is the gene editing tool CRISPR.
This blog post examines how CRISPR technology can be used to help with two keys aspects of the fight – as a rapid way of testing whether someone currently has the disease and as a potential therapeutic that could be used to eradicate the virus in COVID-19 patients.
CRISPR technology in developing a reliable and rapid COVID-19 diagnostic test
The current standard approach to determine whether a patient is infected with the COVID-19 virus involves taking a nasal or throat swab which is then sent away for testing in laboratories. The laboratories then make use of polymerase chain reaction (PCR) technology to identify whether genetic material of the virus is present in the sample and use this information to diagnose the patient. It can take up to 72 hours to generate this diagnosis and, whilst the UK government has announced a target to obtain a diagnosis in less than 24 hours from testing, there are concerns that speed of testing is creating a bottleneck that will hinder the test and trace efforts being used to help prevent the arrival of a second peak of infection.
CRISPR has emerged as a technology that may be able to be used to deliver faster COVID-19 tests without sacrificing accuracy. CRISPR is normally associated with genome editing applications, where short pieces of RNA guide an enzyme called Cas9 to cut DNA at targeted locations within a genome. In this sense, Cas9 has often been likened to a pair of “molecular scissors” that can be used to specifically cut user-defined DNA sequences.
In recent years, diagnostic technology involving related enzymes in the CRISPR toolbox called Cas12a and Cas13 have been developed. Like Cas9, Cas12a also directly binds and cuts target DNA sequences. What makes Cas12a different, however, is that once it starts cutting the DNA target it also begins cleaving nearby single-stranded DNA in a non-specific manner. Thus, rather than being described as “molecular scissors” some researchers have labelled Cas12a as a kind of “molecular paper shredder”. Cas13 also has a similar non-specific shredding activity, however it acts on RNA rather than DNA.
Scientists have been able to harness the promiscuous cleavage activity of Cas12a and Cas13 to detect and report on the presence of particular target nucleic acids, such as those nucleic acids introduced into a patient’s cell upon COVID-19 infection. This works by including a single-stranded “reporter” nucleic acid in the CRISPR-based assay, which delivers a detectable signal upon cleavage. If the CRISPR-Cas12a or Cas13 detects COVID-19 nucleic acids in the sample, it will cleave the reporter nucleic acid, generate a detectable signal and allow the diagnosis of COVID-19 infection.
Advantages over the current standard PCR-based technique for detecting COVID-19 include increased speed and the fact that the tests use commercially available “off the shelf” reagents without the need for expensive laboratory equipment. In one recent academic publication, it was reported that a highly accurate COVID-19 diagnosis could be obtained within 30-40 minutes using this CRISPR technology. The fact that there is no need for any specialised laboratory equipment to obtain a result further raises the exciting possibility that such CRISPR-based tests could eventually be released as kits that could be used at home.
Although these kits are not available to consumers yet, there has been rapid progress in getting these tests to a point where the public can access them. In May, it was announced that the consumer arm of GlaxoSmithKline has teamed up with CRISPR pioneer Jennifer Doudna’s company Mammoth Biosciences in developing this new COVID-19 diagnostic. Also in May, another company – Sherlock Biosciences – announced it had received Emergency Use Authorisation from the FDA for its CRISPR kit to be used in laboratories.
As testing continues to be at the heart of any successful coronavirus containment strategy, the development of faster and simplified ways of obtaining a diagnosis holds great promise in our fight against this disease. With these CRISPR-based tests moving closer to consumer availability, there is great hope that they will realise this promise and revolutionise the speed in COVID-19 testing as humanity continues to tackle this pandemic.
CRISPR technology as a potential COVID-19 treatment
Most reports regarding the potential of using CRISPR technology as a therapeutic to treat diseases focus on harnessing its genome editing power to try and fix genetic diseases. The use of CRISPR to treat genetic diseases took a step closer to being realised earlier this year as scientists attempted to treat an inherited form of blindness in the first ever clinical trial in humans involving CRISPR.
COVID-19, however, is not a genetic disorder that would be amenable to CRISPR genome editing in the same way as the clinical trial it being carried out to treat the inherited form of blindness. Nevertheless, scientists have been making early stage attempts to find innovative ways of treating COVID-19 that make use of CRISPR technology.
The novel coronavirus causing COVID-19 belongs to a family of RNA viruses which enter the cells of infected patients, releases its RNA genome into the cytoplasm and synthesises further copies of viral RNA molecules to assemble new viruses that infect other cells. Recently, a laboratory from Stanford University published a paper describing the use CRISPR in conjunction with a particular RNA-targeting Cas13 enzyme to target and degrade specific viral RNA molecules released by the coronavirus. This technique, which the authors named ‘PAC-MAN’ (Prophylactic Antiviral CRISPR in huMAN cells), was demonstrated to elicit strong repression of viral sequences in an in vitro setting.
As admitted by the authors of the paper, the PAC-MAN technique is still at the proof of concept stage and there remains a long road ahead to demonstrate that this technique can also be used safely and effectively in humans before it could be considered as a treatment for COVID-19. Nevertheless, this CRISPR-based technology adds to the growing list of potential therapies that are being attempted as researchers scramble to find an effective treatment for COVID-19 and look for ways to prevent future pandemics.
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